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Gonçalves, Francisco Q.; Lopes, João P.; Silva, Henrique B.; Lemos, Cristina; Silva, António C.; Gonçalves, Nélio; Tomé, Ângelo R.; Ferreira, Samira G.; Canas, Paula M.; Rial, Daniel; Agostinho, Paula; Cunha, Rodrigo A.
Neurobiology of disease, December 2019, 2019-12-00, 20191201, 2019-12-01, Letnik: 132Journal Article
Adenosine A2A receptors (A2AR) overfunction causes synaptic and memory dysfunction in early Alzheimer's disease (AD). In a β-amyloid (Aβ1-42)-based model of early AD, we now unraveled that this involves an increased synaptic release of ATP coupled to an increased density and activity of ecto-5′-nucleotidase (CD73)-mediated formation of adenosine selectively activating A2AR. Thus, CD73 inhibition with α,β-methylene-ADP impaired long-term potentiation (LTP) in mouse hippocampal slices, which is occluded upon previous superfusion with the A2AR antagonist SCH58261. Furthermore, α,β-methylene-ADP did not alter LTP amplitude in global A2AR knockout (KO) and in forebrain neuron-selective A2AR-KO mice, but inhibited LTP amplitude in astrocyte-selective A2AR-KO mice; this shows that CD73-derived adenosine solely acts on neuronal A2AR. In agreement with the concept that ATP is a danger signal in the brain, ATP release from nerve terminals is increased after intracerebroventricular Aβ1-42 administration, together with CD73 and A2AR upregulation in hippocampal synapses. Importantly, this increased CD73 activity is critically required for Aβ1-42 to impair synaptic plasticity and memory since Aβ1-42-induced synaptic and memory deficits were eliminated in CD73-KO mice. These observations establish a key regulatory role of CD73 activity over neuronal A2AR and imply CD73 as a novel target for modulation of early AD. •A2AR-mediated control of LTP requires CD73-mediated catabolism into adenosine.•β-amyloid caused synaptic and memory dysfunction involving CD73/A2AR upregulation.•A2AR overfunction needs increased ATP release and CD73-convertion to adenosine.•CD73 is a key controller of A2AR and a novel target to interfere with AD.
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